The goal of this IPCAVD program is to develop Ad26/Env vaccines for HIV-1 by a highly collaborative and multifaceted research program involving leading investigators in academia and industry. Our overall hypothesis is that an optimized Ad26/Env mosaic vaccine will induce highly functional antibodies that will protect humans against acquisition of multiple HIV-1 clades. The significance of this program is the potential actual development of a safe and effective global HIV-1 vaccine, the unparalleled commitment of a major pharmaceutical company to this HIV-1 vaccine, and the opportunity for major scientific advances in our understanding of immune correlates of protection. In our current IPCAVD program (U19 AI096040), we have developed alternative serotype adenovirus vectors, bioinformatically optimized HIV-1 mosaic antigens, and stable Env gp140 protein immunogens. We have shown that the Ad26-Env/Gag/Pol prime, Env gp140 protein boost (Ad26/Env) vaccine afforded unprecedented protective efficacy against acquisition of infection following heterologous SIVmac251 challenges in rhesus monkeys, as well as robust protection against SHIV-SF162P3 challenges. Protection correlated with polyfunctional antibody responses as determined by systems serology. We have also advanced the Ad26/Env, Ad26/MVA, and Ad26/MVA/Env mosaic vaccines into phase 1/2a clinical trials in the United States, East Africa, South Africa, and Thailand. Over the next 5 years of this IPCAVD program, we propose to define the extent and mechanism of protection achieved by our lead Ad26/Env vaccine regimen in rhesus monkeys, to advance our lead vaccine regimen into phase 2b/3 efficacy studies in humans, and to develop an improved next generation HIV-1 vaccine candidate. To accomplish the goals of this IPCAVD program, we propose the following Projects and Cores: Project 1. Preclinical Development of Ad26/Env Vaccines for HIV Project 2. Manufacturing and Clinical Development of Ad26/Env Vaccines for HIV Core A. Administrative Core Core B. Immunology Core Core C. NHP Core